Pharmacogenetic Studies Pharmacogenetics involves the study of host susceptibility and environmental exposures in cancer development. The unique contribution of this discipline is that common genes are studied, and the role of the environment is more explicit because the mechanism of the putative polymorphic gene of interest is known. The study base is the population, but family studies often complement this work. We primarily focus on molecular epidemiology studies involving lung and lymphoproliferative cancers and occasionally involving special exposures such as dioxin. The major aim is to identify and better understand genetic components that contribute to major cancers. The studies involve interdisciplinary efforts and emphasize the integration of epidemiological, genetic, and laboratory approaches. Lung Cancer: GEB has been a pioneer in studies aimed at identifying a genetic component to common cancers using epidemiological study designs. Early work emphasized polymorphic genes (e.g., CYP2D6, GSTM1) that are hypothesized to activate or detoxify carcinogens and thereby alter an individual's susceptibility to cancer when exposed to a specific agent. Lung cancer is a logical focus for these studies, because the environmental agent is well characterized (i.e., tobacco smoking), although only a minority of heavy smokers develop the disease. Furthermore, somatic gene mutations are well documented in lung cancer, and relatives of people who develop the cancer are also at increased risk. To better understand the postulated genetic component to smoking-related cancer we have conducted case-control studies of lung cancer with extensive biospecimen collection; studies of determinants of the cancer in nonsmokers; studies of the cancer in different geographic, occupational, and ethnic groups; and studies of consecutive surgical cases with emphasis on tissue collection in order to characterize somatic genes, and are currently involved in studies to evaluate whether genes contribute to precursor conditions (i.e. emphysema) or the key exposure (i.e. smoking). Families with lung and other smoking-related cancers have been studied, although suitable large, multi generation families are challenging to accrue because of the death toll for smoking-related diseases. Integrated Studies: In our single largest study, we are investigating the genetic determinants of lung cancer and smoking in a multi-hospital, population-based case-control study of lung cancer with sufficient power to detect gene-environment interactions, biospecimen collection to allow interdisciplinary study of biomarkers from normal and neoplastic tissue, tissue collection from lung cancer sib pairs, and the planned study of genetic determinants of smoking in controls. This study is currently in the field in Milan, Italy.We participate in NCl's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Study, which is a cohort study of 70,000 individuals in which large numbers of lung cancer cases will be identified over the next few years. Currently studies of the genetic determinants of emphysema and the genetic determinants of smoking are planned. A related component, the National Lung Cancer Screening Trial (NLST) is planning to randomize over 50,000 high risk subjects to chest x-ray or helical CT scan, a promising new imaging technique that may detect lung cancer in an early curable stage. We intend to conduct a study to collect biospecimens on the screened population so both early markers and molecular determinants of benign vs. malignant outcomes can be explored. We also plan to address the hypothesis of a genetic component to smoking itself. We have examined genetic polymorphisms affecting dopamine regulation and receptor stimulation as candidates for influencing genetic susceptibility to cigarette smoking. Preliminary findings suggest that the dopamine transporter gene (DATI), which governs the reuptake of dopamine from the neuronal synapse, and the D2 dopamine receptor gene (DRD2), which is a postsynaptic receptor, may interact to influence smoking behavior. This finding suggests that smoking may be influenced by an interplay among multiple genes affecting dopaminergic reuptake and receptor stimulation. Understanding the mechanisms of dopaminergic genes in smoking may facilitate development of improved strategies to prevent smoking and help smokers quit the habit. Other Tumors and Exposures: We collaborate in studies of genetic susceptibility for a wide variety of other tumors. We have recently described a role for GSTTI as well as NAT1/NAT2 in prostate cancer. Unusual population exposures provide an opportunity to test for the role of mechanistically plausible genes in cancer causation. One example is the industrial accident that contaminated Seveso, Italy, with the highly toxic compound 2,3,7 ,8-tetrachloro-dibenzo(p )-dioxin (TCDD). Two decades after the incident, a population-based study was designed to determine current TCDD levels in healthy individuals from the contaminated zones and surrounding areas. We previously showed that TCDD levels were significantly higher in women than in men in both the contaminated and surrounding areas. Future research will examine the relation between risk of dioxin-related chloracne and cancer to dose as well as to expression of polymorphisms of candidate genes, including CYPlAl and the Ah receptor.